Department of Anesthesiology and Critical Care Medicine, Charité-Universitätsmedizin Berlin Campus Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, Berlin 12203, Germany.
Computational Molecular Design, Zuse-Institut Berlin, Takustrasse 7, Berlin, 14195, Germany.
Science. 2017 Mar 3;355(6328):966-969. doi: 10.1126/science.aai8636.
Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological (rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral μ-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide-binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3',5'-monophosphate inhibition in vitro It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.
阿片受体的非选择性激活可提供止痛作用，但也会导致严重的中枢和肠道副作用。我们假设，利用阿片受体-配体相互作用的病理性（而非生理性）构象动力学，可能会产生没有不良反应的配体。通过在低 pH 值（损伤组织的特征）下进行计算机模拟，我们设计了一种激动剂，由于其低酸离解常数，该激动剂可选择性地激活疼痛产生源处的外周 μ 阿片受体。与传统阿片类药物芬太尼不同，该激动剂具有 pH 敏感性结合、通过荧光共振能量转移的异三聚体鸟苷酸结合蛋白 (G 蛋白) 亚基解离以及体外腺苷 3'，5'-单磷酸抑制作用。它在具有不同类型炎症性疼痛的大鼠中产生了局限于损伤的镇痛作用，而没有表现出呼吸抑制、镇静、便秘或成瘾潜力。
